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Abstract

Ellis-van Creveld syndrome (EVC) is a chondral and ectodermal dysplasia characterized
by short ribs, polydactyly, growth retardation, and ectodermal and heart defects.
It is a rare disease with approximately 150 cases reported worldwide. The exact prevalence
is unknown, but the syndrome seems more common among the Amish community. Prenatal
abnormalities (that may be detected by ultrasound examination) include narrow thorax,
shortening of long bones, hexadactyly and cardiac defects. After birth, cardinal features
are short stature, short ribs, polydactyly, and dysplastic fingernails and teeth.
Heart defects, especially abnormalities of atrial septation, occur in about 60% of
cases. Cognitive and motor development is normal. This rare condition is inherited
as an autosomal recessive trait with variable expression. Mutations of the EVC1 and EVC2 genes, located in a head to head configuration on chromosome 4p16, have been identified
as causative. EVC belongs to the short rib-polydactyly group (SRP) and these SRPs,
especially type III (Verma-Naumoff syndrome), are discussed in the prenatal differential
diagnosis. Postnatally, the essential differential diagnoses include Jeune dystrophy,
McKusick-Kaufman syndrome and Weyers syndrome. The management of EVC is multidisciplinary.
Management during the neonatal period is mostly symptomatic, involving treatment of
the respiratory distress due to narrow chest and heart failure. Orthopedic follow-up
is required to manage the bones deformities. Professional dental care should be considered
for management of the oral manifestations. Prognosis is linked to the respiratory
difficulties in the first months of life due to thoracic narrowness and possible heart
defects. Prognosis of the final body height is difficult to predict.

Disease name

Ellis-van Creveld syndrome (MIM 225500)

Chondroectodermal dysplasia

Mesoectodermal dysplasia

Definition

Ellis van Creveld syndrome (EVC) is an autosomal recessive skeletal dysplasia, with
inter- and intra-familial variability, characterized by short ribs, short limbs, postaxial
polydactyly, and dysplastic teeth and nails. Congenital heart defects occur in 60%
of the individuals. Mutations in the EVC1 and EVC2 genes are associated with this syndrome.

Epidemiology

EVC is a rare disease. The exact prevalence remains unknown. About 100 cases have
been reported between the first full description of the syndrome in 1940, by R. Ellis
and S. Van Crefeld [1], and 1968 [2]. Since 1968, approximately 50 other cases have been reported in the literature. EVC
is found with an increased frequency among the Amish community in Lancaster Country,
Pennsylvania, US, where the largest pedigree has been described: 52 cases in 30 sib
ships [3].

Clinical description

EVC phenotype is variable and affects multiple organs. General detailed descriptions
of the clinical manifestations in limited series or single reports are available [3-10].

Prenatal abnormalities may be early discovered, after the 18th gestation week; they include narrow thorax, marked shortening of the long bones, hexadactyly
of hands and feet, and cardiac defect [11,12], leading to discussing the diagnosis of short rib-polydactyly syndromes (cf. below).
Increased first-trimester fetal nuchal translucency thickness in association with
ECV has been described at 13th week of gestation [12].

After birth, the cardinal features usually present are: 1) disproportionate small
stature whith increasing severity from the proximal to distal portions of the limbs,
and shortening of the middle and distal phalanges (Figure 1); 2) polydactyly affecting hands (uni [exceptional: [13]] – or, usual, bilateral) and, occasionally, the feet (Figure 2); 3) hidrotic ectodermal dysplasia mainly affecting the nails, hair and teeth; 4)
congenital heart malformations occurring in about 50–60% of cases and comprising of
single atrium, defects of the mitral and tricuspid valves, patent ductus, ventricular
septal defect, atrial septal defect and hypoplastic left heart syndrome. The presence
of congenital heart disease may support the diagnosis of the EVC syndrome and appears
to be the main determinant of longevity [6,14].

Figure 1. Patient at the age of 5 years showing long narrow chest and shortness of the limbs.

Several inconstant additional clinical findings are described, including strabismus,
epi- and hypospadias, cryptorchidism [3], and thoracic wall and pulmonary malformations [16]. Renal abnormalities are found in very rare cases with agenesis, dysplasia, megaureter
and nephrocalcinosis. Lethal nephronophthisis has been reported only once, in a patient
with short limbs, short ribs, abnormal teeth and polydactyly (considered as EVC) [17], but this diagnosis may be discussed. Hematologic abnormalities have also been rarely
reported: one case with dyserythropoiesis [18] and another associated with perinatal myeloblastic leukemia [19]. Head circumference and mental developement in EVC are normal.

Because of the overlap between EVC and other short ribs-chondrodysplasias, and because
molecular studies are only recently available and non-constantly performed, some old
reports of EVC associated with exceptional features should be carefully read, since
they may be mixed with publications that evidently do not deal with the EVC syndrome.

The possibility of manifestations in heterozygous carriers has been discussed for
a long time. From the observation of the large Amish kindred, McKusick concluded that
there is no heterozygous manifestation of EVC [3]. However, other authors described polydactyly in relatives of four unrelated EVC
families [20,21]. Spranger and Tariverdian [22] described a father of an EVC patient with fingers and teeth abnormalities, and then
reviewed other reports of possible heterozygous manifestations. The Weyers acrofacial
dysostosis, an autosomal dominant disorder described in 1952, is characterized by
variable extremities and facial features. This condition has been found to be associated
with EVC and EVC2 mutations that, finally, confirmed that Weyers dysostosis represents the heterozygous
expression of the mutation, which, in homozygous form, causes the autosomal recessive
disorder EVC [23,24].

Skeletal features

A variety of radiological skeletal features may be observed, including retarded bone
maturation, fusion of the hamate and capitate bones of the wrist, defect of the lateral
aspect of the proximal part of the tibia (knock-knees), cubitus valgus, hypoplastic
cubitus, supernumerary carpal bone centre, clinodactyly of the 5th finger, fusion of the 5th and 6th metacarpals, disturbance in bone modeling of the metacarpals and/or phalanges. Bone
age is usually retarded.

Etiology

The EVC gene was previously localized by linkage analysis to the distal short arm of chromosome
4 [25,26], in an area proximal to other chondrodystrophias. Mutations in this gene have been
identified in EVC individuals from the Amish cases and from other pedigrees (Mexico,
Equador and Brazil) [23]. But the screening of the 21 EVC coding exons in 58 patients with EVC permitted to identify only 13 patients with homozygous
mutations. Among the remaining 45 cases, no mutation in one or two allele was identified
[27]. The cDNA analysis of fibroblast RNA from three of these patients was also normal.
These observations had raised the possibility of genetic heterogeneity. A second gene,
EVC2, was identified in an Ashkenasi child, immediately adjacent to EVC (named EVC1 or EVC), in a head to head configuration [28]. Expression of the gene is found in heart, placenta, lung, liver and skeletal muscle.
EVC2 spans 166.4 kb and shares a common promoter region with EVC. The transcriptional start sites of EVC and EVC2 are separated by only 1643 bp. There is no significant sequence homology between EVC and EVC2 at either protein or nucleic levels. The EVC2 gene encodes a protein predicted to have one transmembrane segment, three coiled-coil
regions, and one RhoGEF domain (SMART). The EVC2 protein has significant sequence
homology with the tail domains of class IX non muscle myosins (BLAST). Mutations in
the LIMBIN gene, a bovine orthologue of EVC2, are associated with bovine chondrodysplastic dwarfism [28]. Affected EVC individuals with mutations in EVC or EVC2 are phenotypically indistinguishable [27]. An interesting recent work with sequencing EVC and EVC2 in a series of 65 EVC patients identified EVC mutations in 20 families and EVC2 mutations in 25 families [29]. No mutation has been identified in 20/65 families but as none of these individuals
had consanguineous parents (even if it was possible that some of these cases were
misdiagnosed), this has lead to evidence for a genetic heterogeneity in EVC syndrome.
As previously mentioned, heterozygous mutations in the EVC or EVC2 genes also cause Weyers acrofacial dysostosis, an allelic disorder, showing autosomal
dominant inheritance.

Diagnostic methods

The clinical diagnosis is based on observation of the symptoms and manifestations
described above and supported by the skeletal survey. The definitive diagnosis is
molecular, based on homozygosity for a mutation in the EVC and EVC2 genes by direct sequencing.

Differential diagnosis

EVC belongs to the short rib-polydactyly group (SRP). These SRPs are all autosomal
recessive disorders that have been classified into types (Saldino-Noonan syndrome,
type I; Majewski syndrome, type II; Verma-Naumoff syndrome, type III; Beemer-Langer
syndrome, type IV; and Jeune Dystrophy). They are characterized by hypoplastic thorax
due to short ribs, short limbs, frequent polydactyly and visceral abnormalities, and
are discussed prenatally. Radiographically and histologically, SRP III (Verma-Naumoff
syndrome, OMIM 263510) most resembles some forms of EVC [30,31]. The question of SRP being due to mutation in the EVC1 gene was excluded by Takamine et al. [32].

Postnatally, the essential differential diagnoses include Jeune dystrophy, McKusick-Kaufman
syndrome and Weyers syndrome. Jeune dystrophy (MIM 208500) is characterized by thoracic
dystrophy, shortening of the extremities and generalized bone dysplasia. Similarities
and differences of patients with EVC and Jeune dystrophy have been stressed [33,34]. There are no specific constant features to confirm the diagnosis of presumptive
EVC but some features, including congenital heart disease, supernumerary digits and
ectodermal dysplasia will mostly support the diagnosis of EVC syndrome than Jeune
dystrophy. EVC and McKusick-Kaufman syndrome (MKK, MIM 236700), both recessively inherited
disorders, share postaxial polydactyly and congenital heart defect. Distinguishing
characteristics are the osteochondrodysplasia and ectodermal anomalies in EVC syndrome,
and hydro metrocolpos in MKK syndrome. MKK is caused by mutations in a gene on chromosome
20p12, encoding a protein similar to members of the chaperonin family. Mutation in
the same gene causes Bardet-Biedl syndrome-6 [35]. Weyers acrodental dysostosis (OMIM 193530) is, as mentioned above, the heterozygotous
manifestation of the EVC gene. Disproportionate dwarfism, heart defect and thoracic dysplasia are not present
in this autosomal dominant condition.

Genetic counseling

EVC syndrome is an autosomal recessive disorder, with a mendelian risk of 25% for
subsequent pregnancies.

Prenatal diagnosis

EVC may be detected prenatally by ultrasound examination. The association of several
structural fetal defects in the late first trimester, including narrow thorax, short
and bowed long bones, rounded metaphyses, postaxial polydactyly, and cardiac defect
may suggest the diagnosis ECV. Increased nuchal translucency thickness has been described
associated with ECV [12]. In case of potential recurrence, prenatal diagnosis using molecular genetic techniques
is, in theory, feasible, on DNA extracted from chorionic villus samples.

Management

The management of EVC is multidisciplinary. Symptomatic management is mostly required
in the neonatal period, including treatment of the respiratory distress due both to
narrow chest and heart failure. Neonatal teeth should be removed because they may
impair the feeding. In infancy and early adulthood, general and specialized pediatric
follow-up are also required: the short stature is considered resulting of chondrodysplasia
of the legs and the possible treatment with growth hormone is considered ineffective.
It is important to notice, however, that the association of growth hormone deficiency
and ECV has been reported in one patient and, in this case, the growth hormone treatment
had a favorable effect on growth [36]. The possibility of bones deformity, especially knee valgus with depression of the
lateral tibial plateau and dislocation of the patella [37], needs regular orthopedic follow-up. Dentists play an important role in control of
dental and oral manifestations. Dental treatment must be performed under prophylactic
antibiotic coverage with consideration for the high incidence of cardiac defects in
EVC patients. In addition, as in other chondrodysplasias, rare narrowing of the spinal
canal can occur and justify a regular follow-up during adult life.

Prognosis

Although there is no systematic follow-up EVC series reported, the prognosis is linked
to the respiratory difficulties in the first months of life and these difficulties
are related to thoracic narrowness and possible heart defect.

We insist on the fact that the cognitive development in EVC syndrome is normal. Prognosis
of the final body height in individual patients with EVC is difficult to predict,
as the rare publications of adult EVC cases report a variable final stature, from
119 cm [8] to 161 cm [4].

Unresolved questions

Clinical features

The clinical spectrum of EVC syndrome is not well delineated at present. There are
no specific constant features in EVC syndrome: some of them are usually present but
their absence does not exclude the diagnosis. Depending on the diagnostic criteria,
some patients may be recognized as EVC and other patients not. In the literature,
there are many cases described as EVC syndrome in which the diagnosis is uncertain,
and some of them definitely represent other entities. The reported data are limited
to small series. Careful collection of case history, genotype-phenotype correlation
with the two known genes and patient follow-up will provide supplementary information
and further delineation of the EVC syndrome, and distinction from the other short
rib-polydactyly syndromes.

Molecular mechanism

ECV is associated with a genetic heterogeneity and EVC1 and EVC2 do not account for the totality of EVC cases. Further studies are needed to elucidate
other genes involved in EVC manifestations. They could also contribute to unraveling
specific molecular processes that lead to the phenotypic manifestations of ECV.